Whitehead scientists reach major genome goal

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With the completion of the first comprehensive genetic map of the mouse genome, scientists at the Whitehead Institute for Biomedical Research have reached a major milestone in the international Human Genome Project.

The mouse map appeared in the March 14 issue of Nature along with a comprehensive genetic map of the human genome created by researchers at Genethon in France.

"These two achievements signify the completion of the genetic mapping phase of the Human Genome Project," said Dr. Francis S. Collins, director of the National Center for Human Genome Research of the National Institutes of Health. "Now, the once-daunting task of mapping a disorder can be accomplished in a modest-size lab in a few months."

Dr. Eric S. Lander, director of the Whitehead/MIT Center for Genome Research, explained that it is crucial to map both mouse and human genomes, because much of human disease research is done in laboratory models and the mouse is the best available model. Even before it was finished, the mouse map has permitted analyses of previously intractable genetic traits, providing new insights into the origins of asthma, hypertension, colon cancer, diabetes and epilepsy.

"Genetic maps provide very powerful tools for exploring the origins of polygenic diseases, that is, diseases resulting from the interaction of multiple genes," Dr. Lander said. "Understanding how different genes work together to affect the timing, severity and outcome of diseases such as cancer and diabetes will lead to new strategies for disease prevention and therapy."

The mouse genome contains essentially the same complement of 100,000 genes found in the human, with typical mouse genes being about 75 percent identical to their human counterparts. There is a high probability that any disease-related genes identified in mice will play a role in the same biological process in human disease.

The Whitehead mouse map consists of 7,377 markers and provides dense coverage of all 20 chromosomes of the mouse genome. "You can think of these markers as bookmarks spaced throughout the mouse genome," Dr. Lander said. "When we're searching for a new disease gene in mice, we look for markers that tend to be inherited along with the disease.

"For example, when we discover that the disease gene occurs in the final pages of chapter 10 (because the disease is always inherited along with a bookmark lodged in chapter 10, or a marker residing on chromosome 10), then it becomes much easier to search through nearby pages and find the gene."

The vast majority (6,580) of the markers on the Whitehead map consist of highly variable regions called simple sequence length polymorphisms (SSLPs). These regions consist of a simple alternating two-letter DNA pattern: CACACA. Such SSLPs have formed the backbone for the genetic maps of both mouse and man.

"These CA repeats are especially useful because they are highly variable in length," explained Dr. William F. Dietrich, the first author of the Nature paper. "Genetic experiments in mice often consist of mating two different strains of mice, one with known susceptibility to the disease of interest and one resistant to the disease. We can follow inheritance patterns in the offspring of these mice by tracking the lengths of the CA repeats. Differences between the two parental strains allow us to zero in on the disease gene. The same phenomenon makes it easy to use CA repeats to trace inheritance in human families."

"With the completion of dense maps of mouse and man, it is now possible to dissect virtually any genetic trait," Dr. Lander added. "Although it would be possible to extend these maps further, they are more than adequate for genetic studies and it is now time to turn to the determination of the complete 3-billion-letter DNA sequence of these two mammals."

The co-leaders of the mouse genome mapping group at the Whitehead Institute are Dr. Dietrich and Dr. Joyce Miller. Among their collaborators on the Nature paper are Drs. Neal G. Copeland and Nancy A. Jenkins of the Mammalian Genetics Laboratory, NCI-Frederick Cancer Research and Development Center in Frederick, MD. This work was supported by the NIH Center for Human Genome Research.

A version of this article appeared in MIT Tech Talk on March 20, 1996.